Biology subjects

Holley, S. M.

Publications and source records attributed to Holley, S. M..

5 recordsLinked to original sources

bioRxiv2025

Striatal cell-type specific stability and reorganization underlying agency and habit

Goal-directed behavior is guided by learned action-outcome associations, allowing actions to adapt when outcomes change. With repetition, behavioral control shifts toward habit, enabling more automatic action execution, but reducing flexibility to outcome changes. Here, we used longitudinal, cellular-resolution calcium imaging, chemogenetics, instrumental conditioning, and the outcome devaluation test to ask how dorsomedial striatum D1+ and D2/A2A+ neurons contribute to the formation of goal-directed behavior and habit. DMS D1+ neurons stably encode instrumental actions, carry information about behavioral engagement and organization, and develop and maintain action-reward representational similarity and conjunctive activation with learning. Correspondingly, these neurons are critical for action-outcome learning and goal-directed decision making. In contrast, one ensemble of DMS A2A+ neurons transiently encodes actions during early action-outcome learning and another slowly starts to encode actions as habits form. Similarly, DMS A2A+ neurons transiently mediate action-outcome learning and become dispensable for goal-directed decision making. Thus, action-outcome associations are learned through DMS D1+ and A2A+ neuronal activity but only DMS D1+ neurons maintain support of adaptive, goal-directed decision making. Habit formation is associated with reorganization of A2A+ neuronal encoding. These data reveal a cell-type-specific dissociation between stable v. reorganizing striatal action representations paralleled by persistent v. transient contributions to goal-directed control.

neuroscience↗

bioRxiv2024

Corticostriatal Maldevelopment in the R6/2 Mouse Model of Juvenile Huntington Disease

There is a growing consensus that brain development in Huntingtons disease (HD) is abnormal, leading to the idea that HD is not only a neurodegenerative but also a neurodevelopmental disorder. Indeed, structural and functional abnormalities have been observed during brain development in both humans and animal models of HD. However, a concurrent study of cortical and striatal development in a genetic model of HD is still lacking. Here we report significant alterations of corticostriatal development in the R6/2 mouse model of juvenile HD. We examined wildtype (WT) and R6/2 mice at postnatal (P) days 7, 14, and 21. Morphological examination demonstrated early structural and cellular alterations reminiscent of malformations of cortical development, and ex vivo electrophysiological recordings of cortical pyramidal neurons (CPNs) demonstrated significant age- and genotype-dependent changes of intrinsic membrane and synaptic properties. In general, R6/2 CPNs had reduced cell membrane capacitance and increased input resistance (P7 and P14), along with reduced frequency of spontaneous excitatory and inhibitory synaptic events during early development (P7), suggesting delayed cortical maturation. This was confirmed by increased occurrence of GABAA receptor-mediated giant depolarizing potentials at P7. At P14, the rheobase of CPNs was significantly reduced, along with increased excitability. Altered membrane and synaptic properties of R6/2 CPNs recovered progressively, and by P21 they were similar to WT CPNs. In striatal medium-sized spiny neurons (MSNs), a different picture emerged. Intrinsic membrane properties were relatively normal throughout development, except for a transient increase in membrane capacitance at P14. The first alterations in MSNs synaptic activity were observed at P14 and consisted of significant deficits in GABAergic inputs, however, these also were normalized by P21. In contrast, excitatory inputs began to decrease at this age. We conclude that the developing HD brain is capable of compensating for early developmental abnormalities and that cortical alterations precede and are a main contributor of striatal changes. Addressing cortical maldevelopment could help prevent or delay disease manifestations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/618500v1_ufig1.gif" ALT="Figure 1000"> View larger version (38K): org.highwire.dtl.DTLVardef@16db9eborg.highwire.dtl.DTLVardef@c9329borg.highwire.dtl.DTLVardef@1198fc1org.highwire.dtl.DTLVardef@12ce530_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Enhancer-targeted CRISPR-Activation Rescues Haploinsufficient Autism Susceptibility Genes

Autism Spectrum Disorder (ASD) is a highly heritable condition with diverse clinical presentations. Approximately 20% of ASDs genetic susceptibility is imparted by de novo mutations of major effect, most of which cause haploinsufficiency. We mapped enhancers of two high confidence autism genes - CHD8 and SCN2A and used CRISPR-based gene activation (CRISPR-A) in hPSC-derived excitatory neurons and cerebral forebrain organoids to correct the effects of haploinsufficiency, taking advantage of the presence of a wildtype allele of each gene and endogenous gene regulation. We found that CRISPR-A induced a sustained increase in CHD8 and SCN2A expression in neurons and organoids, with rescue of gene expression levels and mutation-associated phenotypes, including gene expression and physiology. These data support gene activation via targeting enhancers of haploinsufficient genes as a therapeutic intervention in ASD and other neurodevelopmental disorders.

neuroscience↗

bioRxiv2021

A bidirectional corticoamygdala circuit for the encoding and retrieval of detailed reward memories

Adaptive reward-related decision making often requires accurate and detailed representation of potential available rewards. Environmental reward-predictive stimuli can facilitate these representations, allowing one to infer which specific rewards might be available and choose accordingly. This process relies on encoded relationships between the cues and the sensory-specific details of the reward they predict. Here we interrogated the function of the basolateral amygdala (BLA) and its interaction with the lateral orbitofrontal cortex (lOFC) in the ability to learn such stimulus-outcome associations and use these memories to guide decision making. Using optical recording and inhibition approaches, Pavlovian cue-reward conditioning, and the outcome-selective Pavlovian-to-instrumental transfer (PIT) test in male rats, we found that the BLA is robustly activated at the time of stimulus-outcome learning and that this activity is necessary for sensory-specific stimulus-outcome memories to be encoded, so they can subsequently influence reward choices. Direct input from the lOFC was found to support the BLA in this function. Based on prior work, activity in BLA projections back to the lOFC was known to support the use of stimulus-outcome memories to influence decision making. By multiplexing optogenetic and chemogenetic inhibition we performed a serial circuit disconnection and found that the lOFC[->]BLA and BLA[->]lOFC pathways form a functional circuit regulating the encoding (lOFC[->]BLA) and subsequent use (BLA[->]lOFC) of the stimulus-dependent, sensory-specific reward memories that are critical for adaptive, appetitive decision making.

neuroscience↗

bioRxiv2021

Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington's Disease Mouse Striatum

Huntingtons disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

neuroscience↗